A bcl-xl inhibitor and pharmaceutical uses thereof

Abstract

The application discloses a BCL-XL inhibitor and a pharmaceutical application thereof, and belongs to the field of pharmacy. A compound provided by the application has a structure as shown in formula Ia. The compound can effectively combine with BCL-XL protein and further inhibit the activity of the BCL-XL protein. The compound can be used for preparing a medicine for combining with BCL-XL, and a medicine for preventing and / or treating a disease (for example, cancer, an autoimmune disease and the like) related to the activity or expression amount of the BCL-XL protein, and has a wide clinical application prospect. The compound has good pharmacological properties, high stability and high drug possibility, and the preparation method of the compound is simple, the yield is high, the cost is low, and the compound is suitable for industrialized production.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a BCL-XL inhibitor and its pharmaceutical uses. Background Technology

[0002] Cancer is the leading cause of death and a serious threat to human health, with high incidence and mortality rates. Studies show that one of the reasons for tumor development and drug resistance is the high expression of the BCL-XL gene and protein in human cells, which prevents the body from properly clearing abnormal genes and inhibits apoptosis. Previous research has shown that apoptosis plays a negative regulatory role in tumor development and can inhibit tumor cell proliferation. The ratio of BCL-XL in the heterodimer formed by BCL-XL and Bak determines whether a cell survives after receiving apoptotic signals. If the expression level of BCL-XL decreases, the effect of the pro-apoptotic gene Bak cannot be balanced, leading to apoptosis.

[0003] BCL-XL, a member of the BCL-2 family, is an anti-apoptotic protein overexpressed in various cancer cells, making it a promising target for anti-tumor therapy. Current research reports that BCL-XL activity is associated with the treatment of autoimmune diseases and various cancers, including bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, primitive lymphocytic leukemia, follicular lymphoma, T-cell or B-cell-derived lymphomas, melanoma, granulocytic leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, and spleen cancer. Developing drugs that can effectively bind to and further inhibit BCL-XL protein activity is of great significance for the clinical treatment of autoimmune diseases and various cancers.

[0004]

[0005] Currently, several BCL-XL inhibitors have been reported, such as A-1155463 and A-1331852. Chinese patent application number 201810379582.7 also discloses compound 15 with the aforementioned structure, which can bind to the BCL-XL protein and thus be used as a drug to treat diseases related to BCL-XL protein activity or expression levels. However, to meet the substantial clinical demand, the development of more novel BCL-XL inhibitors is of great significance. Summary of the Invention

[0006] The object of this invention is to provide a novel compound and its use in the preparation of a medicament that binds to BCL-XL, and in medicaments for the prevention and / or treatment of diseases related to BCL-XL protein activity.

[0007] This invention provides a compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, the structure of which is shown in Formula Ia:

[0008]

[0009] Ring A is selected from a benzene ring or a 5-6 membered aromatic heterocycle, wherein the benzene ring or aromatic heterocycle is not substituted or is surrounded by one, two or three independent R rings. A1 replace;

[0010] The R mentioned A1 Selected from -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycle); wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle is not substituted or is surrounded by one, two, or three independent R... A2 replace;

[0011] Each R A2 Independently selected from hydrogen, halogen, =O, carboxyl, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -NH2, -NH(C) 1～10 alkyl), -N(C) 1～10 Alkyl)(C 1～10 alkyl);

[0012] The R2 is selected from hydrogen, -OH, -O(C) 1～10 Alkyl groups, -NH2, -NH(C) 1～10 alkyl), -N(C) 1～10 Alkyl)(C 1～10 alkyl);

[0013] R1 is selected from

[0014] X is selected from N or CR x ;

[0015] R x Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, -OH, -O(C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 alkyl);

[0016] R11 Selected from hydrogen, halogens, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -OH, -O(C) 1～10 Alkyl groups, -NH2, -NH(C) 1～10 alkyl), -N(C) 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)NH(C) 1～10 Alkyl), -C 0～2 Alkylene-C(O)N(C) 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 alkylene-O-(6- to 10-membered aromatic ring), -C 0～2 alkylene-O- (5- to 10-membered aromatic heterocycles);

[0017] R 12 Selected from hydrogen, halogens, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, -OH, -O(C) 1～10 Alkyl groups, -NH2, -NH(C) 1～10 alkyl), -N(C) 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)NH(C) 1～10 Alkyl), -C 0～2 Alkylene-C(O)N(C) 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 alkylene-O-(6- to 10-membered aromatic ring), -C 0～2 alkylene-O- (5- to 10-membered aromatic heterocycles);

[0018] Or, R 11 R 12Together with the atoms attached thereto, they form 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic ring, or 5-10 membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle is not substituted or is modified by one, two, or three independent hydrogens, halogens, oxo groups, or -C groups. 2～10 alkenyl, -C 2～10 alkynyl group, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, -OH, -O(C) 1～10 Alkyl groups, -NH2, -NH(C) 1～10 alkyl), -N(C) 1～10 Alkyl)(C 1～10 Alkyl) substitution.

[0019] Furthermore, the A ring is a benzene ring or a nitrogen-containing 5-6 membered aromatic heterocycle, wherein the benzene ring or the nitrogen-containing 5-6 membered aromatic heterocycle is not substituted or is replaced by one, two or three independent R rings. A1 Replace; R A1 As described in Equation Ia.

[0020] Furthermore, the structure of the compound is shown in Formula IIa and Formula IIb:

[0021]

[0022] Among them, R A1 R1 and R2 are as described in equation Ia.

[0023] Furthermore, the R2 is selected from hydrogen, -OH, -O(C 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 alkyl).

[0024] Furthermore, R2 is selected from... -OH.

[0025] Furthermore, the R mentioned A1 Selected from -(3- to 6-membered heterocyclic alkyl groups), -C 0～2 Alkylene (5-6 membered aromatic heterocycle); wherein the heterocyclic alkyl or aromatic heterocycle is not substituted or is surrounded by one, two, or three independent R... A2 replace;

[0026] Each R A2 Independently selected from halogens, =O, carboxyl groups, and -C 1～6 Alkyl; preferably, each R A2 Independently selected from =O, carboxyl, and -C 1～6 alkyl.

[0027] Furthermore, the R mentioned A1 Selected from Preferably, the R A1 Selected from

[0028] Furthermore, R1 is selected from...

[0029] X is selected from N or CH;

[0030] R 11 Selected from hydrogen and halogens;

[0031] R 12 Selected from hydrogen, halogens, -C 1～6 Alkyl, -C(O)NH(C) 1～6 Alkyl), -C(O)N(C 1～6 Alkyl)(C 1～6 alkyl);

[0032] Or, R 11 R 12 Together with the atoms attached to it, they form a benzene ring.

[0033] Furthermore, R1 is selected from... Preferably, R1 is

[0034] Furthermore, the compound is selected from:

[0035]

[0036] The present invention also provides a method for preparing the above-mentioned compound, the method comprising the following steps:

[0037]

[0038] (1) Compound F-1 reacts with lithium bis(trimethylsilyl)amino to give compound F-2;

[0039] (2) Compound F-2 reacts with compound 12 to give compound F-3;

[0040] (3) Compound F-3 reacts with compound 13 to give compound F1; or, compound F-3 reacts with compound 14 to give compound F2; or, compound F-3 reacts with compound 15 to give compound F3;

[0041] Alternatively, the method may include the following steps:

[0042]

[0043] (a) Compound F1-1 reacts with compound F1-2 to give compound F1-3;

[0044] (b) Compound F1-3 reacts with compound F1-4 to give compound F1-5;

[0045] (c) Compound F1-5 reacts with phosphorus oxychloride first, and then with methylamine hydrochloride to give compound F1-6;

[0046] (d) Compound F1-6 reacts with compound 1 to give compound 1F.

[0047] The present invention also provides the use of the above-described compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its tautomer, in the preparation of a medicament that binds to the BCL-XL protein.

[0048] Furthermore, the drug is a drug for the prevention and / or treatment of diseases related to the activity or expression level of BCL-XL protein.

[0049] Furthermore, the diseases associated with BCL-XL protein activity or expression levels are autoimmune diseases or cancer.

[0050] The present invention also provides a pharmaceutical composition, which is a formulation prepared by adding pharmaceutically acceptable excipients to the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its tautomer as the active ingredient.

[0051] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0052] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0053] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0054] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a～b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C 1～6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms.

[0055] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of member atoms. For example, C 1～6An alkyl group is an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group can be straight-chain or branched. A representative branched alkyl group has one, two, or three branches. The alkyl group may optionally be substituted by one or more substituents as defined herein. Alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. The alkyl group may also be part of other groups, such as C1-C6 alkoxy groups.

[0056] "Cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms, no heterocyclic atoms, and a single ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.

[0057] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0058] "Halogen-substituted alkyl" refers to an alkyl group in which one or more hydrogen atoms can be substituted by one or more halogen atoms. For example, halogen-substituted C 1～6 Alkyl refers to an alkyl group containing 1 to 6 carbon atoms in which one or more hydrogen atoms are replaced by one or more halogen atoms.

[0059] "Heterocyclic" and "heterocyclic alkyl" refer to saturated or partially saturated rings containing at least one heteroatom in the cyclic atoms; where the heteroatom refers to nitrogen, oxygen, or sulfur atoms.

[0060] "Aryl" and "aromatic ring" are used interchangeably, both referring to a fully carbon ring with a conjugated π-electron system.

[0061] "Aromatic heterocycles" refer to aromatic rings in which the ring-forming atoms contain at least one heteroatom; where the heteroatom refers to nitrogen, oxygen, or sulfur atoms.

[0062] "Stereoisomers" include enantiomers and diastereomers.

[0063] A tautomer is a special type of functional group isomer, resulting from the rapid movement of an atom between two positions in a molecule. A pair of tautomers can interconvert, but the more stable isomer is usually the dominant form. Examples include enol and keto tautomers.

[0064] Compounds of the present invention The tautomer is

[0065] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0066] The terms "salt" and "pharmaceutical salt" refer to acidic and / or basic salts formed by the above-described compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-described compounds or their stereoisomers with an appropriate (e.g., equimolar) amount of acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, or by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium.

[0067] The pharmaceutically acceptable excipients described in this invention include pharmaceutically acceptable excipients, carriers, excipients, mediators, or any combination thereof.

[0068] In some embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent to prepare a medicament or pharmaceutical composition for regulating cell function or treating disease. If a group of compounds is used, these compounds may be administered to the test subject simultaneously, separately, or sequentially.

[0069] The compounds provided by this invention can effectively bind to the BCL-XL protein and further inhibit its activity. These compounds can be used to prepare drugs that bind to the BCL-XL protein, as well as drugs for the prevention and / or treatment of diseases related to BCL-XL protein activity or expression levels (e.g., cancer, autoimmune diseases), and have broad clinical application prospects.

[0070] The term "prevention" includes suppressing and delaying the onset of disease, and includes not only prevention before the disease develops, but also prevention of disease recurrence after treatment.

[0071] The term “treatment” means to reverse, alleviate or eliminate the progression of one or more symptoms of a disease or condition to which such term is applied.

[0072] The compounds of this invention have more attractive molecular structures and smaller molecular weights.

[0073] The compound of this invention has good pharmacological properties, good stability, high drug potential, and the preparation method of the compound is simple, with high yield and low cost, making it suitable for industrial production.

[0074] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0075] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0076] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be obtained from commercially available products.

[0077] Unless otherwise specified in the examples, the reaction is carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Room temperature is the optimal reaction temperature, which is 20°C to 30°C. Unless otherwise specified in the examples, M is moles per liter.

[0078] The structure of the compound was determined using nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) were expressed in terms of 10⁻¹⁰. -6 The unit (ppm) is given. NMR determination was performed using a Bruker Avance III 400 and Bruker Avance 600 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methol-d4). The internal standard was tetramethylsilane (TMS). LC-MS determination was performed using a Shimadzu LC-MS 2020 (ESI) system. HPLC determination was performed using a Shimadzu LC-20A high-performance liquid chromatograph. MPLC (medium-pressure preparative chromatography) was performed using a Gilson GX-281 reversed-phase preparative chromatograph. Thin-layer chromatography used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, with a thickness of 0.4 mm to 0.5 mm for product separation and purification. Column chromatography generally used Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0079] The reagents described in the examples are abbreviated as follows: Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; Pd(OAc)2: palladium acetate; Pd2(dba)3: tris(dibenzylacetone)dipalladium; XantPhos: 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene; S-Phos: 2-biscyclohexylphosphine-2',6'-dimethoxy-1,1'-diphenyl; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; DIPEA: N N-Diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; HOBt: 1-hydroxybenzotriazole; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMAP: 4-dimethylaminopyridine; TCDI: N,N'-thiocarbonyldiimidazolium; LiHMDS: lithium bis(trimethylsilyl)amino; DMF: N,N-dimethylformamide; THF: tetrahydrofuran; DMSO: N,N-dimethyl sulfoxide.

[0080] Example 1: Synthesis method of compounds F1, F2, and F3 of the present invention:

[0081]

[0082] Step 1: Synthesis of compound F-2

[0083]

[0084] Compound F-1 (200.00 mg, 1.29 mmol) was added sequentially to a 50 mL flask, followed by 10 mL of diethyl ether. LiHMDS (3 mL, 1 mol / L) was then added dropwise under ice bath conditions. After the addition was complete, the reaction was stirred at room temperature for 2 hours to quench the reaction (monitored by LC-MS). The pH was adjusted to 6-8 with 1 mol / L hydrochloric acid solution. The aqueous layer was collected and concentrated under reduced pressure to obtain compound F-2 (crude product). LC-MS: C 10 H 10 N3, (ESI)[M+H] + :172.1.

[0085] Step 2, Synthesis of Compound F-3

[0086]

[0087] Compound F-2 (crude product), compound 12 (100.00 mg, 584.21 μmol), cesium carbonate (379.68 mg, 1.17 mmol), cuprous iodide (22.25 mg, 116.82 μmol), and DMF (2 mL) were added to a 50 mL reaction flask. The reaction was maintained at 80 °C for approximately 2 hours until the reaction was complete (monitored by LC-MS). The reaction solution was concentrated under reduced pressure to remove impurities, and purified by MPLC to obtain compound F-3 (35.00 mg, 99.38 μmol, 17.01% yield). LCMS: C 17 H 11 BrN3O,(ESI)[M+H] + :352.0.

[0088] Step 3, Synthesis of Compound F1

[0089]

[0090] Under nitrogen protection, compound F-3 (35.00 mg, 99.38 μmol), compound 13 (14.92 mg, 149.07 μmol), cesium carbonate (64.60 mg, 198.76 μmol), Pd(OAc)₂ (11.16 mg, 0.25 mol%), and XantPhos (34.50 mg, 59.63 μmol) were added sequentially to a 50 mL reaction flask. The reaction system was sealed and stirred at 100 °C for 8 hours to quench the reaction (monitored by LC-MS). Extraction was performed using saturated sodium chloride solution (20 mL) and ethyl acetate (3 x 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. Separation was then performed by column chromatography with a petroleum ether / ethyl acetate volume ratio of 1:100 to 1:5. After solvent removal by concentration under reduced pressure, compound F1 was obtained (3.20 mg, 6.98 μmol, 7.02% yield, 81.0% purity). LC-MS: C 21 H 18 N5O2,[M+H] + 372.2; Detected value: 372.2. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.56 (s, ¹H), 9.10 (s, ¹H), 8.16 (t, J = 9.5Hz, ³H), 8.02–7.91 (m, ²H), 7.84 (s, ¹H), 7.78 (d, J = 6.8Hz, ¹H), 3.56 (t, J = 7.8Hz, ²H), 3.09 (d, J = 7.2Hz, ²H), 2.84 (s, ³H). Purity > 80%.

[0091] Following the above synthetic route, replacing compound 13 with the raw materials listed in Table 1 yields compounds F2 and F3.

[0092] Table 1. Compounds F2 and F3

[0093]

[0094] Example 2: Synthesis method of compound 1F of the present invention:

[0095]

[0096] Step 1: Synthesis of compound F1-3

[0097]

[0098] Under nitrogen protection, compound F1-1 (161 mg, 1.00 mmol), pinacol diboronate F1-2 (381 mg, 1.50 mmol), KOAc (196 mg, 2.00 mmol), 1,4-dioxane, water (4 mL / 1 mL), and Pd(dppf)Cl2 (36.59 mg, 50.00 μmol) were added sequentially to a 50 mL reaction flask. The reaction system was sealed and stirred at 100 °C for 5 hours (monitored by LC-MS). The resulting mixture was separated by MPLC, and the solvent was removed by concentration under reduced pressure to obtain compound F1-3 (40 mg, 317.66 μmol, 31.77% yield). The prepared compound was characterized: MS (ESI) m / z = 127.1 (M+1). + .

[0099] Step 2, Synthesis of compound F1-5

[0100]

[0101] Under nitrogen protection, compounds F1-3 (75.07 mg, 311.43 μmol), F1-4 (40 mg, 317.66 μmol), Cs₂CO₃ (253.04 mg, 778.58 μmol), 1,4-dioxane, water (4 mL / 1 mL), and Pd(dppf)Cl₂ (22.79 mg, 31.14 μmol) were added sequentially to a 50 mL flask. The reaction system was sealed, and the reaction was quenched after heating and stirring at 100 °C for 1 hour. Extraction was completed with saturated NaCl solution (20.0 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. The organic phases were purified by MPLC, and the solvent was removed by concentration under reduced pressure to obtain compound F1-5 (30 mg, 123.85 μmol, 39.77% yield). The obtained compound was characterized as follows: MS (ESI) m / z = 243.1 (M+1). +

[0102] Step 3, Synthesis of compound F1-6

[0103]

[0104] Compound F1-5 (30 mg, 123.85 μmol) and phosphorus oxychloride (18.99 mg, 123.85 μmol) were added to a 25 mL flask under ice bath cooling, followed by the slow addition of DIPEA (742.00 mg, 5.74 mmol, 1 mL). The reaction mixture was gradually heated and stirred at room temperature for two hours, then heated to 110 °C and stirred for another two hours. After the reaction was complete (monitored by LC-MS), the reaction mixture was concentrated to dryness. 5 mL of acetonitrile, 0.5 mL of triethylamine, and methylamine hydrochloride (29.02 mg, 429.92 μmol) were added to the intermediate, and the mixture was heated and stirred at 80 °C for 8 hours (monitored by LC-MS). After the reaction was complete, the reaction mixture was concentrated, purified by MPLC, and the solvent was removed by concentration under reduced pressure to give compound F1-6 (10 mg, 36.53 μmol, 33.99% yield). The obtained compound was characterized: MS (ESI) m / z = 274.1 (M+1). +

[0105] Step 4: Synthesis of Compound 1F

[0106]

[0107] Under nitrogen protection, compound F1-6 (10 mg, 36.53 μmol), compound 1 (9.48 mg, 54.80 μmol), Cs₂CO₃ (29.68 mg, 91.33 μmol), 1,4-dioxane, and water (4 mL / 1 mL) were added sequentially to a 25 mL flask. The reaction system was sealed, and the reaction was quenched after heating and stirring at 100 °C for 1 hour. Extraction was completed using saturated NaCl solution (20.0 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was purified by MPLC, and the solvent was removed by concentration under reduced pressure to obtain compound 1F (1.8 mg, 4.91 μmol, 13.45% yield, 97.8% purity). The obtained compound was characterized: MS (ESI) m / z = 367.3 (M+1). + . 1H NMR (400MHz, DMSO-d6) δ9.82 (s, 1H), 9.37 (s, 1H), 8.33-8.24 (m, 3H), 8.17 (d, J = 8.0Hz, 1H) ,8.08(d,J=8.4Hz,1H),7.84-7.78(m,3H),6.96(d,J=2.0Hz,1H),3.94(s,3H),3.32(s,3H).

[0108] The following experimental examples demonstrate the beneficial effects of the present invention.

[0109] Experimental Example 1: Surface Plasmon Resonance (SPR) Combined Experiment of BCL-XL

[0110] 1. Test Methods

[0111] Prepare the running buffers: The protein fixation buffer and running buffer A have the same composition, with NaH₂PO₄ concentration of 10 mM, Na₂HPO₄ concentration of 40 mM, NaCl concentration of 150 mM, Tween 20 content of 0.03%, and pH adjusted to 7.4; Running buffer B has NaH₂PO₄ concentration of 10 mM, Na₂HPO₄ concentration of 40 mM, NaCl concentration of 150 mM, Tween 20 content of 0.03%, DMSO content of 5.00%, and pH adjusted to 7.4. After preparing the running buffers, filter them through a 0.22 μm filter membrane.

[0112] BCL-XL protein fixation: Using protein fixation buffer, BCL-XL was immobilized on an NTA chip via His capture and amino coupling. The NTA chip surface was washed with 50 mM NaOH and 350 mM EDTA at a flow rate of 60.0 μL / min for 60 seconds each time; then activated with 10 mM NiCl2 for 1100 seconds, followed by activation with a 1:1 mixture of EDC (75.00 mg / mL) and NHS (11.50 mg / mL) at a flow rate of 10.0 μL / min for 650 seconds; finally, BCL-XL (0.04 mg / mL) was injected at 4.0 μL / min for 850 seconds. After BCL-XL injection, a 1:1 mixture of EDC (75.00 mg / mL) and NHS (11.50 mg / mL) was crosslinked for 200 seconds at a rate of 10.0 μL / min. Finally, the chip surface was sealed with 1M ethanolamine (pH 8.5) at a rate of 6.0 μL / min for 7 minutes. The final fixation amount of BCL-XL was 4690.00 RU.

[0113] Compound dilution: Dilute the test compound to 100-fold of the desired final concentration with 100% DMSO. After mixing, pipette 4.0 μL into 396 μL of running buffer A and centrifuge at 15000 rpm for 5 minutes to obtain a 1X compound solution containing 1% DMSO for subsequent dilutions. The compound to be tested should be serially diluted 2-fold to 9 concentrations starting from 50 μM (using 200 μL of the compound solution added to 200 μL of running buffer B for 2-fold dilution, resulting in 10 concentration gradients, including one 0 concentration (using running buffer B instead), with an initial concentration of 50 μM). Transfer the diluted compound to a 96-well plate for sample injection.

[0114] Procedure: The experiment was conducted at 25°C using run buffer B at a flow rate of 30.0 μL / min. After equilibration via eight injections of run buffer B, compounds were injected sequentially from lowest to highest concentration, with binding and dissociation times both set at 120 seconds. The syringe was rinsed with 50% DMSO after each injection. Solvent differences caused by DMSO were corrected for using 0.50%, 0.75%, 1.00%, 1.25%, and 1.50% DMSO.

[0115] 2. Test Results

[0116] The response values ​​of the compounds to the BCL-XL protein were analyzed after subtracting the reference channel and the 0 concentration. The affinity Kd was fitted using the steady state affinity model (1:1 binding model) with Biacore T200 Evaluation Software.

[0117] The prepared compounds were subjected to SPR detection according to the above method, and the experimental results are shown in Table 2.

[0118] Table 2. Binding response values ​​of compounds to BCL-XL

[0119] Compound # Kd F3 +

[0120] Note: The table uses "+" to indicate the range of Kd values. Specific information is as follows:

[0121] +: 10μM-100μM;

[0122] -:>100uM.

[0123] Experimental results show that the compounds of this invention can effectively bind to the BCL-XL protein and further inhibit its activity. The compounds of this invention can be used to prepare drugs that bind to BCL-XL, as well as drugs for the prevention and / or treatment of diseases related to BCL-XL protein activity.

[0124] In summary, the compounds provided by this invention can effectively bind to the BCL-XL protein and further inhibit its activity. These compounds can be used to prepare drugs that bind to BCL-XL, as well as drugs for the prevention and / or treatment of diseases related to BCL-XL protein activity or expression levels (e.g., cancer, autoimmune diseases), showing broad clinical application prospects. The compounds of this invention possess excellent pharmacological properties, good stability, high drug development potential, and are simple to prepare with high yield and low cost, making them suitable for industrial production.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the compound is shown in formula IIa or formula IIb: wherein R2is selected from hydrogen, -OH, -NH(C 1～6 alkyl); R A1 is selected from -(3-6 membered heterocycloalkyl), -C 0～2 alkylene-(5-6 membered aromatic heterocycle); wherein said heterocycloalkyl, aromatic heterocycle is unsubstituted or substituted with one or two independent R A2 substituents; each R A2 is independently selected from halogen, =0, carboxyl, -C 1～6 alkyl; R1is 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R2is selected from the group consisting of -OH.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R A1 selected from 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the group consisting of:

5. A process for the preparation of a compound according to claim 4, characterized in that: The method comprises the following steps: (1) compound F-1 reacts with lithium bis(trimethylsilyl)amide to obtain compound F-2; (2) compound F-2 reacts with compound 12 to obtain compound F-3; (3) compound F-3 reacts with compound 13 to obtain compound F1; or, compound F-3 reacts with compound 14 to obtain compound F2; or, compound F-3 reacts with compound 15 to obtain compound F3; Alternatively, the method comprises the following steps: (a) compound F1-1 reacts with compound F1-2 to obtain compound F1-3; (b) compound F1-3 reacts with compound F1-4 to obtain compound F1-5; (c) compound F1-5 first reacts with phosphorus oxychloride, and then reacts with methylamine hydrochloride to obtain compound F1-6; (d) compound F1-6 reacts with compound 1 to obtain compound 1F.

6. Use of the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1-4 in the preparation of a drug for binding to BCL-XL protein.

7. Use according to claim 6, characterized in that: The drug is a drug for preventing and / or treating a disease related to the activity or expression amount of BCL-XL protein.

8. Use according to claim 7, characterized in that: The disease related to the activity or expression amount of BCL-XL protein is an autoimmune disease or cancer.

9. A pharmaceutical composition, characterized by: It is a preparation prepared by taking the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1-4 as an active ingredient, and adding a pharmaceutically acceptable adjuvant.

Images